Abstract
Specific guanine rich nucleic acid sequences can form non-canonical structures, like the four stranded G-quadruplex (GQ). We studied the GQ-forming sequence (named HepB) found in the genome of the hepatitis B virus. Fluorescence-, infrared- and CD-spectroscopy were used. HepB shows a hybrid form in presence of K+, but Na+, Li+, and Rb+ induce parallel structure. Higher concentrations of metal ions increase the unfolding temperature, which was explained by a short thermodynamic calculation. Temperature stability of the GQ structure was determined for all these ions. Na+ has stronger stabilizing effect on HepB than K+, which is highly unusual. The transition temperatures were 56.6, 53.8, 58.5 and 54.4 °C for Na+, K+, Li+, and Rb+ respectively. Binding constants for Na+ and K+ were 10.2 mM and 7.1 mM respectively. Study of three ligands designed in cancer research for GQ targeting (TMPyP4, BRACO19 and PhenDC3) showed unequivocally their binding to HepB. Binding was proven by the increased stability of the bound form. The stabilization was higher than 20 °C for TMPyP4 and PhenDC3, while it was considerably lower for BRACO19. These results might have medical importance in the fight against the hepatitis B virus.
Highlights
IntroductionQuadruplex structures were first identified in the telomere regions[13] and promoter regions of oncogenes in the human genome that indicates their role in o ncogenesis[14,15]
This paper focuses on the stability of this GQ and on the targeting of this GQ with ligands developed for cancer therapy: TMPyP4, BRACO19 and PhenDC3
TMPyP4 was purchased EMD (USA) and ChemCruz (Dallas, USA), BRACO19 and PhenDC3 were purchased from Sigma-Aldrich Kft. (Hungary)
Summary
Quadruplex structures were first identified in the telomere regions[13] and promoter regions of oncogenes in the human genome that indicates their role in o ncogenesis[14,15]. They can be found in the promoters of c-MYC, c-KIT, B-cell lymphoma protein-2 (BCL-2), vascular-endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), retinoblastoma protein (RB), KRAS, hypoxia-induced factor-1 (HIF-1) and human telomeric reverse transcriptase (hTERT), for example[16,17,18]. Due to its high-affinity binding, it has been used in assays to indicate formation of G-quadruplex[26]
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